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A thyroid nodule is managed according to the clinical context, ultrasound (US) findings, and fine needle aspiration (FNA) results. Most thyroid nodules are benign; however, nodule classification is crucial to avoid unnecessary thyroid surgery. We conducted this study to compare the findings of fine-needle aspiration cytology (FNAC) expressed using the Bethesda system with the features of thyroid US classified using the EU-TIRADS classification to assess the risk of malignancy. A descriptive and analytical study involving 99 patients with thyroid nodules followed up in the Department of Endocrinology-Diabetology and Nutrition. Data were collected from medical records and analyzed using SPSS software V21. FNA was performed on 121 nodules using the BETHESDA system. These nodules were classified as malignant, suspicious for follicular neoplasm, and suspicious for malignancy in 5.8%, 5%, and 1.7% of cases, respectively. As for the EU-TIRADS 2017 classification, 59.5% of benign nodules were classified as EU-TIRADS III, whereas 66.7% of malignant nodules were classified as EU-TIRADS V and significantly related to malignant prediction ( P = 0.000). The size of nodules was significantly correlated to the risk of malignancy ( P = 0.013). Seventy-five percent of nodules with central vascularity were malignant ( P = 0.012). Irregularity of nodule contours was significantly associated with the risk of malignancy, as 30% of nodules with irregular contours were Bethesda VI ( P = 0.003). Hypoechogenicity was found in 77.8% of malignant nodules ( P = 0.004). Additionally, only 9.2% of the nodules were taller than wide, of which 37.5% were malignant ( P = 0.012). For a safe management strategy, US-guided FNAC should be performed on each suspicious thyroid nodule, given the correlation between EU-TIRADS classification features and the risk of malignancy., Competing Interests: The authors declare no conflict of interest., (© 2024 by the authors.)

Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of GNAS , which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of GNAS (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the β6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP., Competing Interests: Authors do not have any conflicts of interest to report., (© 2022 The Authors. Published by Elsevier Inc.)

Background/objective: Functional gonadotroph adenomas (FGAs) are adenomas producing active gonadotropins, follicle-stimulating hormone or luteinizing hormone. Double pituitary adenomas are 2 distinct adenomas occurring in an individual. This report aimed to present an extremely rare case of an FGA, itself an uncommon disorder, co-occurring with a lactotroph adenoma., Case Report: A 33-year-old woman presented with menorrhagia and was found to have ovarian enlargement, large uterine leiomyomas, and bitemporal hemianopsia. Initially, the levels of follicle-stimulating hormone, luteinizing hormone, estradiol, and prolactin were 73.3 mIU/mL (midcycle peak, 2.3-20.9 mIU/L), 3.74 mIU/L (midcycle peak, 8.7-76.3 mIU/L), 1071 pg/mL (midcycle peak 38-649 pg/mL), and 402 ng/mL (2-30 ng/mL), respectively. Pituitary magnetic resonance imaging demonstrated a single sellar mass (2.0 × 2.2 cm). Two months of cabergoline did not reverse visual field deficits; therefore, transsphenoidal resection was performed. Diagnosis of 2 separate adenomas, a gonadotroph and lactotroph adenoma, was confirmed on pathology., Discussion: In this case, gonadotropins did not suppress in response to hyperprolactinemia. Although marked hyperprolactinemia has been associated with functional and clinically silent gonadotroph adenomas in prior cases, this is the first case to confirm an FGA co-occurring with a lactotroph adenoma., Conclusion: In patients who present with elevated gonadotropin levels despite hyperprolactinemia, we suggest considering FGA. Further research is needed to clarify whether there is underdiagnosis of lactotroph adenomas co-occurring with gonadotroph adenomas., Competing Interests: The authors have no multiplicity of interest to disclose, (© 2022 Published by Elsevier Inc. on behalf of the AACE.)

Background: Ménière's Disease, a long-term debilitating disorder has been increasingly found among patients with hypothyroidism. Our study aims to evaluate the prevalence of ménière's disease among hypothyroid patients and assess the interrelationship between patients' symptomology and ménière's disease., Materials and Methods: A cross-sectional study was performed at the endocrinology clinics at Damascus Hospital and Syrian Red Crescent Hospital, Damascus, Syria between September 2021 and January 2022. Patients with hypothyroidism were interviewed using a questionnaire. The questionnaire contained questions about socio-demographic information, hypothyroid history, diagnostic criteria of ménière's disease, chief complaint, medical history, and lab test results. Patients, who reported ménière's disease symptoms, were referred to the otorhinolaryngology clinic for confirmation or exclusion of ménière's disease. At the clinic, patients underwent an otoscopy and a pure tone audiometry, probable and definite ménière's disease was diagnosed accordingly., Results: Of 217 hypothyroid patients included in the sample, 17 (7.8%) were diagnosed with definite ménière's disease and 31 (14.3%) were diagnosed with probable ménière's disease. Hypothyroid symptoms reported among patients diagnosed with definite ménière's disease compared to no diagnosis differed by feeling low (χ2 (1, 217) = 4.014, p = 0.045), and depressive appearance (χ2 (1, 217) = 8.887, p = 0.003). Patients diagnosed with definite ménière's disease, probable ménière's disease, and both definite and probable ménière's disease were more likely to report that their symptoms affected their lifestyle compared to those that reported no effect (χ2 (3, 217) = 62.565, p < 0.001), (χ2 (3, 217) = 31.380, p < 0.001), and (χ2 (3, 217) = 35.542, p < 0.001), respectively., Conclusion: A high number of hypothyroid patients were diagnosed with MD. Clinicians should consider clinically screening for MD among hypothyroid patients presenting to clinics., Competing Interests: None., (© 2022 The Authors.)

Abstract: A group of intracellular nuclear receptors is a protein superfamily including arylhydrocarbon AhR, estrogen ER, androgen AR, thyroid TR and retinoid receptors RAR/RXR as well as molecules with unknown function known as orphan receptors. These proteins play an important role in a wide range of physiological as well as toxicological processes acting as transcription factors (ligand-dependent signalling macromolecules modulating expression of various genes in a positive or negative manner). A large number of environmental pollutants and other xenobiotics negatively affect signaling pathways, in which nuclear receptors are involved, and these modulations were related to important in vivo toxic effects such as immunosuppression, carcinogenesis, reproduction or developmental toxicity, and embryotoxicity. Presented review summarizes current knowledge on major nuclear receptors (AhR, ER, AR, RAR/RXR, TR) and their relationship to known in vivo toxic effects. Special attention is focused on priority organic environmental contaminants and experimental approaches for determination and studies of specific toxicity mechanisms. [Copyright &y& Elsevier]

During the prolonged phase of critical illness, the ongoing hypermetabolic response leads to loss of lean tissue mass. Although the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, most endocrine interventions attempting to correct the hormone balance have shown to be ineffective and their indiscriminate use is even harmful. Thus, a detailed understanding of the neuroendocrinology of the stress response is warranted, especially as the acute and chronic phases show remarkable differences. In the acute stress response, low circulating peripheral anabolic hormone levels, despite an actively secreting pituitary, are indicative of peripheral resistance to the anterior pituitary hormones. By contrast, the pulsatile secretion of anterior pituitary hormones is uniformly decreased in the prolonged phase of the disease, leading to proportionally reduced concentrations of peripheral anabolic hormones. As hypothalamic secretagogues can restore the pulsatile secretion of the anterior pituitary and increase peripheral target hormones, tissues are at least partially sensitive to the anterior pituitary hormones in this phase of illness. Therefore, a combination of hypothalamic secretagogues that reactivates the anterior pituitary to a greater extent could be a more physiological and effective strategy to induce anabolism in patients with prolonged critical illness. [Copyright &y& Elsevier]

Somatostatin (SST) was firstly discovered as a hypothalamic hormone inhibiting GH secretion. Despite its broad inhibitory effects on both endocrine and exocrine secretions, natural SST has limited therapeutic potential owing to its short plasma half-life. The synthesis of the first two metabolically stabilized and more potent SST analogs (octreotide and lanreotide) established the use of SST peptide therapy. The discovery of the five SST receptor (sst1–5) subtypes in the 1990s further enhanced our understanding of the biological roles of SST, created new therapeutic opportunities and highlighted the limitation of ‘classical’ SST analogs, which act mainly via receptor subtype 2 and are unable to reproduce all actions of native SST. To diminish these limitations, new SST analogs highly selective for particular receptor subtypes, together with so-called ‘universal’ analogs acting on multiple receptor subtypes, have been developed. These compounds have shown promise in preclinical studies and might further advance the use of SST analog therapy in the future. The development of SST analogs coupled to radioisotopes or cytotoxic drugs, which allows the selective destruction of tumor cells overexpressing sst receptors, constitutes another field of progress. [Copyright &y& Elsevier]

The anterior pituitary is derived from Rathke’s pouch arising from the oral ectoderm. The initial apparently uniform precursor cells proliferate and differentiate into six different cell types that are present in mature gland by integrative interactions between different signaling molecules and transcription factors. This system provides an opportunity to understand gene regulation in the cellular processes of precursor cell proliferation, determination, and differentiation events during organogenesis. Recent studies have made significant advances in our appreciation of the molecular mechanisms by which transcription factors regulate these cellular processes. [Copyright &y& Elsevier]

The Prophet of Pit-1 (PROP1) gene encodes a paired class homeodomain transcription factor that is exclusively expressed in the developing mammalian pituitary gland. PROP1 function is essential for anterior pituitary organogenesis, and heritable mutations in the gene are associated with combined pituitary hormone deficiency in human patients and animals. By cloning the bovine PROP1 gene and by comparative analysis, we demonstrate that the homeodomains and carboxyl termini of mammalian PROP1 proteins are highly conserved while the amino termini are diverged. Whereas the carboxyl termini of the human and bovine PROP1 proteins contain potent transcriptional activation domains, the amino termini and homeodomains have repressive activities. The bovine PROP1 gene has four exons and three introns and maps to a region of chromosome seven carrying a quantitative trait locus affecting ovulation rate. Two alleles of the bovine gene were found that encode distinct protein products with different DNA binding and transcriptional activities. These experiments demonstrate that mammalian PROP1 genes encode proteins with complex regulatory capacities and that modest changes in protein sequence can significantly alter the activity of this pituitary developmental transcription factor. [Copyright &y& Elsevier]

The wide spectrum of naturally occurring mutations able to activate the thyrotropin (TSH) receptor provides a useful tool to approach the structure of the active state(s) of the glycoprotein hormone receptors. Here we show that the side-chain of the highly conserved N7.49 (Asn 674) in TM7 is mandatory for activation of the TSH receptor, not only by TSH, but also by a panel of eight natural and two artificial activating mutations. Basal activity levels of the mutants were significantly decreased by suppression of the side-chain of N7.49 (N7.49A double mutants). In addition, comparative effects of the N7.49A substitution on the ten mutants demonstrate that basal activity and agonist- or mutation-stimulated activity might involve different structural changes. [Copyright &y& Elsevier]

Background: Subclinical hypothyroidism (SCH) often leads to alterations in lipid profile, which may negatively impact humans health. Whether lipids in turn affect the natural history of SCH is unknown. We aimed to assess the association between longitudinal changes in serum lipid levels and the natural history of SCH., Methods: This retrospective cohort study using data from the REACTION study included 581 patients with SCH who were enrolled between July 1, 2011, and December 19, 2014, with a median follow-up of three [IQR, 2·86-3·21] years. Patients with missing data or conditions that can affect thyroid function were excluded. Changes in serum lipid levels were calculated from serum lipid measurements 3 years apart and classified in two ways: 1) the first, second, and third tertiles of the difference between baseline and follow-up and 2) the percent change from baseline, namely, serum lipid decrease ≥ 25%, minor change, and serum lipid increase ≥ 25%. The natural history of SCH includes regression to euthyroidism, SCH persistence, or progression to overt hypothyroidism (OH). Odds ratios (ORs) were estimated by multivariable logistic regression. Validation was performed on data from a health management cohort study conducted from January 1, 2012, to December 31, 2016, with a median follow-up of two [IQR, 1·92-2·08] years. After using the same inclusion and exclusion criteria as the REACTION cohort study, 412 patients with SCH were eligible for the validation analysis., Findings: There were 132 (22·7%) men and 449 (77·3%) women in the study, with a median age of 56 [IQR,49-62] years. During follow-up, 270 (46·5%), 266 (45·8%), and 27 (4·6%) patients had regression to euthyroidism, persistent SCH, and progression to OH, respectively. Both grouping manners showed a significant association between changes in lipid levels and the natural history of SCH. A total cholesterol (TC)-level increase was independently associated with a greater risk of progression to OH (OR for ≥ 25% TC increase vs. minor change: 5·40; 95% CI 1·46-21·65), whereas TC-level declines increased the likelihood of regressing to euthyroidism (OR for ≥ 25% TC decrease vs. minor change: 3·45; 95% CI 1·09-12·43). Similarly, the likelihood of regression according to changes in triglyceride (TG) levels exhibited a consistent trend with that according to TC-level changes. A similar pattern of association was observed in the validation cohort., Interpretation: Changes in serum lipid levels in SCH are associated with future progression or regression risk, suggesting that the changes in serum lipid levels may affect the natural history of SCH. Clinicians should pay attention to the long-term control of serum lipids levels in populations with SCH, which may benefit thyroid function., Funding: This work was supported by grants from the National Key Research and Development Program of China (2017YFC1309800), the National Natural Science Foundation (81430020, 82070818), and the "Outstanding University Driven by Talents" Program and Academic Promotion Program of Shandong First Medical University (2019LJ007)., Competing Interests: All authors declare no competing interests., (© 2022 The Author(s).)

Background/objective: Although retinoid-associated central hypothyroidism has been reported on several occasions, there are very few studies on retinoid-associated central adrenal insufficiency. Here, we present the case of a patient with alitretinoin-induced central hypothyroidism and adrenal insufficiency., Case Report: An 86-year-old man with a diagnosis of cutaneous T-cell lymphoma, treated with oral alitretinoin 30 mg po daily, topical steroids, and ultraviolet light therapy presented to the emergency department with generalized weakness, decreased energy, orthostasis, and unexplained falls. Thyroid-stimulating hormone (TSH) was 0.31 mIU/L (normal range: 0.4-4.4) from 1.93 before alitretinoin therapy, whereas free thyroxine was 5.7 pmol/L (normal range: 8-18) and the AM cortisol was 40 nmol/L (normal range: 120-535); these values were suggestive of central hypothyroidism and adrenal insufficiency. Adrenocorticotropic hormone (ACTH) was not measured because of a laboratory error. Alitretinoin was stopped, and one dose of hydrocortisone 100mg IV was initiated, followed by maintenance doses of oral hydrocortisone 20mg qam and 10mg qpm. Levothyroxine (50μg ) daily was started 24 hours later. After stopping hydrocortisone for 24 hours, the AM cortisol and ACTH levels were 406 nmol/L and 2.18 pmol/L (normal range:1.6-13.9), respectively. He was discharged on thyroid hormone replacement therapy and glucocorticoids. Repeat thyroid function tests 6 weeks later showed a TSH of 0.4 mIU/L, and free thyroxine of 9.7 pmol/L., Discussion: Alitretinoin activates nuclear receptors called retinoic acid receptors and retinoid X-receptors. Retinoic acid receptors and retinoid X-receptors are widely expressed in the anterior pituitary gland. RXR-selective ligands such as retinoids can suppress TSH secretion, resulting in central hypothyroidism. Retinoids have also been shown to decrease ACTH secretion, which can result in central adrenal insufficiency., Conclusion: Although central adrenal insufficiency and hypothyroidism have not been commonly reported in patients taking retinoids, they should always be considered when caring for these patients., Competing Interests: The authors have no multiplicity of interest to disclose., (© 2022 Published by Elsevier Inc. on behalf of the AACE.)

Objectives: Verifying new reagent or calibrator lots is crucial for maintaining consistent test performance. The Institute for Quality Management in Healthcare (IQMH) conducted a patterns-of-practice survey and follow-up case study to collect information on lot verification practices in Ontario., Methods: The survey had 17 multiple-choice questions and was distributed to 183 licensed laboratories. Participants provided information on materials used and approval/rejection criteria for their lot verification procedures for eight classes of testing systems. The case study provided a set of lot comparison data and was distributed to 132 laboratories. Responses were reviewed by IQMH scientific committees., Results: Of the 175 laboratories that responded regarding reagent lot verifications, 74% verified all tests, 11% some, and 15% none. Of the 171 laboratories that responded regarding calibrator lot verifications, 39% verified all calibrators, 4% some, and 57% none. Reasons for not performing verifications ranged from difficulty performing parallel testing to high reagent cost. For automated chemistry assays and immunoassays, 23% of laboratories did not include patient-derived materials in reagent lot verifications and 42% included five to six patient materials; 58% of laboratories did not include patient-derived materials in calibrator lot verifications and 23% included five to six patient materials. Different combinations of test-specific rules were used for acceptance criteria. For a failed lot, 98% of laboratories would investigate further and take corrective actions. Forty-three percent of laboratories would accept the new reagent lot in the case study., Conclusion: Responses to the survey and case study demonstrated variability in lot verification practices among laboratories., Competing Interests: None., (© 2022 The Authors.)

Objective: To assess the association between vitamin B12 (B12) deficiency and the prevalence of fatigue and prespecified neurologic symptoms in patients with fibromyalgia., Patients and Methods: A retrospective chart analysis of patients diagnosed with fibromyalgia in the years 2015-2020 was performed. The values of B12 were collected. The chart reviews assessed reported fatigue and neurologic symptoms, including brain fog, memory loss, cognitive impairment, paresthesias, numbness, and tingling, to assess their correlation with B12 levels. Concurrent vitamin D and thyroid-stimulating hormone levels were reviewed to assess their association with fibromyalgia., Results: A total of 2142 patients with fibromyalgia with documented levels of B12 and vitamin D were included. Of them, 42.4% had B12 deficiency (<400 ng/L). Fatigue and memory loss were more common in the B12 deficiency group. After adjusting for vitamin D levels, B12 deficiency remained statistically significantly associated with the presence of fatigue (odds ratio, 1.39; 95% confidence interval, 1.11-1.75; P =.004)., Conclusion: This is the first study to report the association of B12 in patients with fibromyalgia complaining of fatigue. This symptom was prevalent in our group of patients with fibromyalgia with B12 deficiency, regardless of whether the cutoff point was 400 or 350 ng/L., (© 2022 The Authors.)

Objective: Pituitary corticotroph macroadenomas, which account for 7% to 23% of corticotroph adenomas, rarely present with apoplexy. This report aimed to describe a patient with a sparsely granulated corticotroph tumor (SGCT) presenting with apoplexy and remission of hypercortisolism., Case Report: A 33-year-old male patient presented via ambulance with sudden onset of severe headache and nausea/vomiting. Physical examination revealed bitemporal hemianopsia, diplopia from right-sided third cranial nerve palsy, abdominal striae, facial plethora, and dorsal and supraclavicular fat pads. Magnetic resonance imaging demonstrated a 3.2-cm mass arising from the sella turcica with hemorrhage compressing the optic chiasm, extension into the sphenoid sinus and cavernous sinus. Initial investigations revealed a plasma cortisol level of 64.08 (reference range [RR], 2.36-17.05) mcg/dL. He underwent emergent transsphenoidal surgery. Pathology was diagnostic of SGCT. Postoperatively, the following laboratory findings were found: (1) cortisol level, <1.8 ug/dL (RR, 2.4-17); (2) adrenocorticotropic hormone level, 36 pg/mL (RR, 0-81); (3) thyroid-stimulating hormone level, 0.07 uIU/mL (RR, 0.36-3.74); (4) free thyroxine level, 1 ng/dL (RR, 0.8-1.5); (5) luteinizing hormone level, <1 mIU/mL (RR, 1-12); (6) follicle-stimulating hormone level, 1 mIU/mL (RR, 1-12); and (7) testosterone level, 28.8 ng/dL (RR, 219.2-905.6), with ongoing requirement for hydrocortisone, levothyroxine, testosterone replacement, and continued follow-up., Discussion: Corticotroph adenomas are divided into densely granulated, sparsely granulated, and Crooke cell tumors. Sparsely granulated pattern is associated with a larger tumor size and decreased remission rate after surgery., Conclusion: This report illustrates a rare case of hypercortisolism remission due to apoplexy of an SGCT with subsequent central adrenal insufficiency, hypothyroidism, and hypogonadism., (© 2022 AACE. Published by Elsevier Inc.)

Background/objective: Lyme disease, the most common vector-borne infection in the United States, causes multisystem inflammation. We describe a patient who presented with symptoms of Lyme disease, carditis, and thyroiditis., Case Report: A 53-year-old woman developed fatigue and dyspnea on exertion 1 month after returning from a trip to Delaware. Her electrocardiogram (ECG) showed first-degree atrioventricular (AV) block with a P-R interval up to 392 milliseconds, in the setting of elevated free thyroxine and undetectable thyroid-stimulating hormone levels. Lyme serology was positive. She was hospitalized and started on ceftriaxone. During the second day of hospitalization, AV block worsened to second-degree Mobitz type II but converted back to first-degree AV block after a few hours. Her 24-hour I-123 thyroid uptake and scan revealed markedly diminished I-123 uptake of 1.2%. On day 4, the P-R interval improved, and she was discharged on doxycycline for 3 weeks. P-R interval on ECG and repeated thyroid function tests were normal after finishing antibiotic treatment., Discussion: In our patient, known exposure to the vector, a classic rash on the chest, improvement in the symptoms, and normalization of thyroid function tests after antibiotic therapy support Lyme infection as a cause of carditis and painless, autoimmune thyroiditis., Conclusion: Our case highlights the importance of considering Lyme disease as a cause of painless, autoimmune thyroiditis, especially in patients with concurrent cardiovascular involvement., (© 2022 AACE. Published by Elsevier Inc.)

Background: Transient thyrotoxicosis has been documented in the setting of hyperemesis gravidarum (HG) with elevated human chorionic gonadotropin (hCG) levels. Thyroid storm in pregnancy is rarer and typically associated with autoimmune hyperthyroidism. We described thyroid storm in a primigravid 18-year-old patient due to hCG level elevation secondary to HG, which resolved in the second trimester of pregnancy., Case Report: Our patient presented with vomiting, hyperthyroidism, and cardiac and renal dysfunction at 16 weeks' gestation. She was clinically found to have a thyroid storm, with undetectable thyroid-stimulating hormone (TSH) and a free thyroxine level of >6.99 ng/dL. The hCG level was elevated at 246 030 mIU/L (9040-56 451 mIU/L). She was treated with methimazole, saturated solution potassium iodide, and propranolol. Because thyroid autoantibodies were absent, thyroid ultrasound yielded normal results, and thyroid function testing results rapidly improved as the hCG level decreased, the medications were tapered and ultimately discontinued by day 10 of hospitalization. The thyroid function remained normal after discharge., Discussion: Because hCG and TSH have identical alfa subunits and similar beta subunits, hCG can bind to the TSH receptor and stimulate thyroxine production. The hCG level peaks at around 8-14 weeks of gestation, correlating with decreased TSH levels in this same time frame. This case emphasizes the relevant physiology and importance of timely and thorough evaluation to determine the appropriate management, prognosis, and follow-up for patients with thyroid storm in the setting of HG., Conclusion: Although transient thyrotoxicosis is documented in patients with HG, thyroid storm is rare, and our case illustrates a severe example of these comorbidities., (© 2022 AACE. Published by Elsevier Inc.)

Background: Subacute thyroiditis (SAT) followed by Graves disease (GD) is a rare condition. We report the case of a patient with recurrent SAT with human leukocyte antigen (HLA)-associated predisposition to GD., Case Report: A 28-year-old Japanese woman presented with neck pain and hyperthyroidism symptoms. We observed elevated C-reactive protein and thyroid hormone levels, along with a high erythrocyte sedimentation rate. Further, anti-thyroid-stimulating hormone receptor antibody was undetected, and thyroid glands were heterogeneous and hypoechoic. These findings confirmed a diagnosis of SAT. The patient was treated with prednisone (starting dose, 30 mg), and clinical and laboratory data suggested an improvement. Six months later, the patient presented with recurrent clinical and biochemical features of hyperthyroidism (thyroid-stimulating hormone level, 0.003 mIU/mL; free thyroxine level, 3.14 ng/dL; and TSH receptor-stimulating autoantibodies, 220%). The patient was diagnosed with GD and was successfully treated with methimazole. Eleven years later, the patient was diagnosed with simultaneous SAT and GD. HLA-typing revealed that the patient possessed characteristic alleles associated with susceptibility to GD, such as HLA-DRB1∗04:03 and ∗15:01 , DQB1∗03:02:01 and 06:02:01 , and HLA DPB1∗05:01 alleles., Discussion: The occurrence of SAT may trigger thyroid antigen release and lead to the onset of GD in patients who are genetically predisposed to this autoimmune disorder., Conclusion: For certain patients, the diagnosis of GD should be considered in case of recurrent hyperthyroidism and history of resolved SAT., (© 2021 AACE. Published by Elsevier Inc.)

Background: Antithyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of thyrotoxicosis. Agranulocytosis is a rare but lethal adverse effect of antithyroid medications. We have reported 2 cases of MMI-induced agranulocytosis with similar risk factors that likely predisposed them to this adverse reaction., Case Report: Case 1 involved a 71-year-old woman, with a history of Graves disease, who presented with an altered mental status. She was recently discharged on 40 mg of MMI twice daily, and she continued this dose for 2 months. She was readmitted and found to have neutropenic fever in the setting of MMI-induced agranulocytosis. MMI was discontinued, and she was started on filgrastim. Her cell counts gradually improved, and she was subsequently discharged.Case 2 involved a 68-year-old woman, with a history of Graves disease, who presented with severe back pain, nausea, and vomiting. She was recently discharged on 10 mg of MMI twice daily, which was increased to 10 mg 3 times a day. She was readmitted to the hospital because of a septic shock in the setting of pneumonia, colitis, bacteremia, and MMI-induced agranulocytosis. A bone marrow biopsy showed a polyclonal infiltrate with up to 85% plasma cells. Despite treatment with antibiotics, filgrastim, and continuous renal replacement therapy, she ultimately passed away., Discussion: Although these cases had differing outcomes, they shared similar features and risk factors, including older age, female sex, and relatively higher doses of MMI., Conclusion: Close follow up and awareness of risk factors, such as age, female sex, and higher doses of MMI, may decrease the risk of MMI-induced agranulocytosis and fatal outcomes., (© 2021 AACE. Published by Elsevier Inc.)

Background/objective: The development of Graves disease (GD) after subacute thyroiditis (SAT) is rare, with approximately 31 reported cases, of which only 5 occurred in men. We describe a case of GD diagnosed based on newly elevated thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone (TSH) receptor autoantibody (TRAb) levels after SAT., Case Report: A 32-year-old Chinese man presented with right anterior neck pain, swelling, sore throat, cough, and fever. He had a diffuse tender goiter but no proptosis, lid lag, or stare. His TSH level was 0.03 mIU/mL (normal range [NR] 0.45-5.33 mIU/mL), serum free thyroxine (FT4) level was 2.40 ng/dL (NR 0.61-1.44 ng/dL), total triiodothyronine (TT3) level was 113 ng/dL (NR 87-178 ng/dL), TSI level was <0.10 IU/L (NR < 0.10 IU/L), and erythrocyte sedimentation rate was 21 mm/h (NR < 15 mm/h). After 7 weeks of prednisone, the symptoms resolved, FT4 level was 0.95 ng/dL, and TT3 level was 91 ng/dL. At 11 weeks after SAT onset, the TSH level was <0.01 mIU/mL, TT3 level was 257 ng/dL, FT4 level was 3.03 ng/dL, TSI level was 1.94 IU/L, then 3.42 IU/L 2 weeks later, TRAb level was 8.72 IU/L (NR < 2 IU/L), and erythrocyte sedimentation rate was 4 mm/h. After 1 month of methimazole, the FT4 level was 1.32 ng/dL and TT3 level was 110 ng/dL. Genetic testing revealed human leukocyte antigen-B35 and DRB1∗15:01 positivity., Discussion: GD after SAT is thought to be due to the activation of thyroid autoimmunity induced by SAT in genetically susceptible individuals., Conclusions: This case illustrates the induction of thyroid autoimmunity after SAT, resulting in GD, supporting TSI and/or TRAb testing if hyperthyroidism recurs. The presence of HLA alleles associated with SAT and GD suggests a genetic contribution to the development of thyroid autoimmunity., (© 2021 AACE. Published by Elsevier Inc.)

Thyrotoxic periodic paralysis is a life-threatening complication of hyperthyroidism characterized by transient episodes of muscle paralysis and hypokalemia, commonly seen in Asian men. We present a rare case of ventricular fibrillation as the initial presentation of thyrotoxic periodic paralysis. ( Level of Difficulty: Intermediate. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Competing Interests: None disclosed.

Maternal thyroid hormones facilitate optimal foetal neurodevelopment; however, the exact role of the thyroid hormones on specific cognitive outcomes is unknown. The present study aimed to investigate associations between maternal thyroid function and neurodevelopmental outcomes in the Seychelles Child Development Study (SCDS) Nutrition 2 cohort ( n 1328). Maternal free thyroid hormones (fT3, fT4 and fTSH) were assessed at 28 weeks' gestation with a range of child cognitive outcomes analysed at 20 months. Dietary iodine intake was analysed for a subset of women through a Food Frequency Questionnaire. Linear regression analysis was used to test associations between serum concentrations of maternal thyroid hormones and child neurodevelopment outcomes. Thyroid hormones were analysed as continuous data and categorised as quintiles. 95% of mothers had optimal thyroid function based on fTSH concentrations. Overall, the present study shows that maternal thyroid function is not associated with neurodevelopmental outcomes in this high fish-eating population. However, a positive association, using quintiles for fT3, was reported for the Mental Developmental Index, between Q3 v. Q4 ( β 0⋅073; P 0⋅043) and for Q3 v . Q5 ( β value 0⋅086; P 0⋅018). To conclude, mothers in our cohort, who largely have optimal thyroid function and iodine intakes, appear able to regulate thyroid function throughout pregnancy to meet neurodevelopmental needs. However, it is possible that minor imbalances of fT3, as indicated from our secondary analysis, may impact offspring neurodevelopment. Further investigation of the relationship between maternal thyroid function and infant neurodevelopment is warranted, particularly in populations with different dietary patterns and thereby iodine intakes., (© The Author(s) 2021.)

Background: Association between clinical effect and serum concentration of amiodarone (AMI) and its active metabolite desethylamidarone (DEA) in patients after surgical ablation (SA) of atrial fibrillation (AF) has not yet been studied., Aims: We wanted to find a correlation between AMI and DEA serum concentration and maintaining sinus rhythm (SR) after SA of AF., Methods: Sixty eight patients with AF who had undergone surgical ablation between 2014 and 2017 were included in a single-centre, prospective, observational study. Maintaining of SR was evaluated by standard 12-lead ECG and 24-hour Holter ECG monitoring at months 1, 3, 6 and 12 following surgery. Therapeutic monitoring of AMI and DEA concentrations was done to optimize therapy and adverse effects were followed up., Results: We have noticed a high success rate in maintaining of SR (overall 83%). The median of serum concentration of AMI was 0.81 mg/L (range 0.16-2.35 mg/L) and DEA 0.70 mg/l (range 0.19-2.63 mg/L). No significant differences were found in the serum concentratration of AMI, DEA or DEA/AMI concentratration ratios between patients with SR and persistent supraventricular tachyarrhythmia except on the second outpatient visit. We observed significant correlation between serum concentration of DEA and thyroid-stimulating hormone elevation., Conclusion: We confirmed the efficacy of AMI and DEA at the measured serum concentrations. However, analysis of these concentrations alone cannot replace assessment of the clinical response for treatment. Establishment of individual AMI (and DEA) concentrations at which the optimal therapeutic response is achieved seems to be advantageous. Therapeutic monitoring of AMI and DEA is helpful in personalised pharmacotherapy after SA of AF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Objective: To describe the rare occurrence of pediatric Hashimoto encephalopathy in 3 patients., Methods: The patients, 9 to 13 years of age, presented with new-onset seizures and other neurologic symptoms, including hemiplegia, aphasia, and memory loss. Thyroid function tests and thyroid antibodies were measured. Magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid analysis, and electroencephalography were also performed., Results: The first patient had a thyroid-stimulating hormone (TSH) level of 60 μIU/mL (range, 0.4-4.5), free T4 of 0.28 ng/dL (range, 0.7-1.6), and thyroid peroxidase antibody (TPO Ab) of 1243 IU/mL (range < 9). The MRI results indicated a hyperintense signal along the gyri and sulci with diffuse leptomeningeal enhancement bilaterally. The second patient had a TSH level of 25 μIU/mL, free T4 level of 0.7 ng/dL, and TPO Ab level of 3340 IU/mL. The MRI result was normal. The third patient, who was already on levothyroxine, had a TSH level of 17 μIU/mL, free T4 level of 0.81 ng/dL, and TPO Ab level of 1200 IU/mL. The MRI result was normal. All patients had significant elevation of protein in the cerebrospinal fluid and background slowing on electroencephalography. All patients were treated with high doses of intravenous methylprednisolone followed by oral prednisone and thyroid hormone replacement., Conclusion: These cases underscore the importance of thyroid function tests with antibodies in children presenting with acute neuropsychiatric manifestations, especially new-onset seizures without any identifiable cause. We believe that this condition is underdiagnosed in children, and a high index of suspicion is recommended., (© 2020 AACE. Published by Elsevier Inc.)

Objective: Tyrosine-kinase inhibitors (TKIs) are chemotherapeutic agents associated with increased thyroid-hormone requirements and altered deiodinase activity. We present the first case to link these findings to the TKI ibrutinib., Methods: Serial thyroid-stimulating hormone (TSH), free-thyroxine (FT4), free-triiodothyronine (FT3), and reverse-triiodothyronine (rT3) levels were assessed., Results: An 80-year-old, 62-kg woman with hypothyroidism secondary to total thyroidectomy for stage I papillary thyroid cancer, on maintenance levothyroxine (LT4) 137 μg daily, presented for follow-up. Compared to one year prior, the patient's weight had increased by 2 kg and TSH from 2.58 to 27.60 μIU/mL (normal: 0.45-4.50 μIU/mL) while on pantoprazole. Ibrutinib, her other medication, had been started seven months prior for chronic lymphocytic leukemia. Despite sequential confirmation of proper LT4 adherence and self-administration, adjustment of LT4 to 150 μg, and discontinuation of pantoprazole, the patient's hypothyroid symptoms worsened, and the TSH was 73.90 μIU/mL six months later. LT4 was increased to 175 μg six days a week and 262.5 μg once weekly. Two months later, the TSH was 3.92 μIU/mL (steady-state condition), FT4 2.32 ng/dL (normal: 0.82-1.77 ng/dL), FT3 1.6 pg/mL (normal: 2.0-4.4 pg/mL), and rT3 69.6 ng/dL (normal: 9.2-24.1 ng/dL). Ibrutinib was discontinued the next month due to gastrointestinal side effects and elevated blood pressure. Four months later, LT4 had been reduced to 150 μg, and the FT4 reached 1.92 ng/dL, FT3 2.0 pg/mL, and rT3 26.6 ng/dL., Conclusion: This report links ibrutinib to increased thyroid-hormone requirements in a thyroidectomized woman whose decreased T3:T4, T3:rT3, and T4:rT3 ratios suggested type 3 deiodinase induction and type 2 deiodinase inhibition., (© 2020 AACE. Published by Elsevier Inc.)

Objective: Concurrent autoimmune disorders, including autoimmune hepatitis (AIH), with Graves disease have been reported. Glucocorticoids can simultaneously lower thyroid hormone levels and treat AIH. Recurrence of hyperthyroidism is associated with recurrence of hepatitis. We present a case of coexisting AIH and Graves thyrotoxicosis, which improved with prednisone, but the thyrotoxicosis recurred during a prednisone taper while the hepatitis stayed in remission., Methods: Evaluation included measurements of liver enzyme levels, thyroid function tests, and thyroid-stimulating antibodies as well as abdominal ultrasound, magnetic resonance imaging, and liver biopsy., Results: A 47-year-old woman presented with nausea and jaundice. Workup showed an aspartate aminotransferase level of 1956 (reference, 10-42) U/L and alanine aminotransferase level of 1634 (reference, 14-54) IU/L. The liver biopsy was consistent with AIH. Nine months later, she reported palpitations, heat intolerance, and weight loss and was diagnosed with Graves disease. The patient received prednisone at 60 mg daily, and the liver and thyroid functions normalized after 1 month. Prednisone was tapered to 5 mg daily. Seven months later, she presented with a thyroid-stimulating hormone level of 0.049 (reference, 0.340-5.6) μIU/mL) and free thyroxine level of 3.96 (reference, 0.58-1.64) ng/dL. Liver enzymes remained at normal levels. Prednisone was increased from 5 to 20 mg to treat hyperthyroidism. The patient was referred for thyroidectomy for a diagnosis of Graves disease with thyrotoxicosis., Conclusion: This case is an example of coexisting autoimmune diseases, Graves disease and AIH, with different clinical courses. Despite initial resolution with glucocorticoid therapy, Graves disease recurred, while AIH stayed in remission., (© 2020 AACE. Published by Elsevier Inc.)

Objective: To describe new and unusual endocrinopathies in children with de novo 18q deletion (18q-) syndrome., Methods: We describe 2 patients who have atypical thyroid conditions and 1 who also developed symptomatic hypocalcemia., Results: The first patient developed hyperthyroidism at the age of 3 years, with a free thyroxine level of 3.9 (range, 0.8-1.8) ng/dL. Thyroid peroxidase antibodies were 262 (range, 0-32) IU/mL, and thyroid-stimulating immunoglobulin antibodies were 384% (range, 0-139%). On low-dose methimazole treatment, she developed hypothyroidism. Thyroid-stimulating hormone (TSH) level was 163 (range, 0.4-4.5) mIU/mL. Moreover, she later developed growth hormone deficiency. The second patient developed hypothyroidism at the age of 4 years, with a TSH level of 46 mIU/mL. However, TSH remained elevated at levels of 10 to 24 mIU/mL for 3 years, despite appropriate treatment, suggesting TSH resistance. She then developed hypocalcemic seizures and was diagnosed with pseudohypoparathyroidism. Her total calcium level was 6.6 (range, 8.5-10.5) mg/dL and parathyroid hormone level was 432 (range, 15-65) pg/dL., Conclusion: The first patient had a mixed picture of autoimmune hypothyroidism and hyperthyroidism, requiring a combination of methimazole and levothyroxine to achieve a euthyroid state. For the second patient, the mild TSH resistance was possibly the early suggestion of a parathyroid hormone resistant state. Although growth hormone deficiency and hypothyroidism are common in patients with 18q- syndrome, the occurrence of hyperthyroidism due to Graves' disease with the coexistence of Hashimoto's hypothyroidism is rare. Pseudohypoparathyroidism has not yet been reported in patients with 18q- syndrome., (© 2020 AACE. Published by Elsevier Inc.)